P360: MEASURABLE/MINIMAL RESIDUAL DISEASE (MRD) STATUS IS THE MOST RELEVANT INDICATOR OF CLINICAL OUTCOME IN MIXED PHENOTYPIC ACUTE LEUKEMIAS (MPAL)
Authors: Prashant Tembhare, Simpy Raj, Sitaram Ghogale, Nilesh Deshpande, Karishma Girase, Gaurav Chatterjee, Sweta Rajpal, Nikhil Patkar, Gaurav Narula, Bhausaheb Bagal, Hasmukh Jain, Manju Sengar, Shripad Banavali, Dhanlaxmi Shetty, Chetan Dhamne, Twinkle Khanka, Steffi Varghese, Shaista Jasdanwala, Navin Khattry, Papagudi G Subramanian, Sumeet Gujral
Journal: HemaSphere (2023)

Background: Mixed phenotypic acute leukemia (MPAL) is a rare disease with poor clinical outcomes. Due to its rarity, a specific risk-adapted therapeutic protocol is not available. Minimal residual disease (MRD) has been proven as a powerful predictor of therapeutic response and higher risk in acute lymphoblastic and myeloid leukemia. However, systematic studies evaluating the clinical value of MRD status and MRD time-points in MPAL are extremely rare. There is no data on the clinical implication of MRD in adult MPAL patients. We present the largest single-centre study on the significance of MRD assessment in MPAL. Aims: Evaluating the clinical relevance of MRD monitoring in MPAL Methods: The study included MPAL patients diagnosed according to WHO2016 criteria from Jan-2015 to June-2022. Cytogenetics was performed using karyotyping and FISH. Molecular studies were performed using targeted next-generation sequencing (NGS). Flow Cytometric MRD (FC-MRD) was estimated at post-induction (PIMRD, day 33) in all patients and post-consolidation (PCMRD, day 78) in PIMRD positive patients. Any detectable value was taken as MRD-positive. Results: We included 120 MPAL patients with median age 15.5-years (range:0.9-66 years; children n=60, <1-18 years and adult n=60, >18-66 years) and M:F-1.8:1. These included 48/120 (40%) B/Myeloid, 15/120 (12.5%) B/T, 56/120 (46.7%) T/Myeloid, & 1/120 (0.8%) B/T/Myeloid subtypes. Pediatric patients were treated with MCP841 & among adult patients, 49 received BFM90 (with tyrosine-kinase inhibitors in BCR::ABL1 positive) & remaining 11 received 3 + 7HIDAC therapy. There was no association between age, sex and immunophenotypic subset with event-free-survival (EFS) and overall-survival (OS). Cytogenetic studies were available in 111 patients and molecular studies in 73 patients. These included BCR::ABL1 (20/111, 18%), KMT2A-rearrangement (5/111, 4.5%), Monosomy7/del7q (10/111, 9%), del5q (4/111, 3.6%), tri/tetrasomies (10/111, 9%), NUP98::NSD1 (2/111, 1.8%), CBFA2T3-GLIS2 (2/111, 1.8%), CEBPA-mutation (9/111, 8.1%), FLT3-ITD(5/111, 4.5%), RAS-mutations (8/111, 7.2%), TP53-mutation (1/111, 0.9%), and other abnormalities (6/111, 5.4%). Among them, Monosomy7/del7q was found to be associated with shorter EFS with Hazard Ratio (HR)-2.23 (median EFS 18.8 versus 72.2 months; p=0.02) and shorter OS with HR-2.6 (median OS 8.8 versus 28.6 months; p=0.02). PI-MRD was positive in 86/120(71.7%) patients with median 1.7% (range:0.0008-58.5%). Among 86 PIMRD positive, PCMRD was available in 70 and was positive in 40/70 (57.1%) patients with median 0.27% (range:0.0005-30.2%). Positive PIMRD was strongly associated with shorter EFS with HR-3.12 (median EFS 21.4 months vs. not reached; p=0.0004) and shorter OS with HR-3.5 (median OS 26.5 months versus not reached; p=0.002) (Figure-1). Positive PCMRD was also strongly associated with shorter EFS (HR-2.4; median EFS 16.5 vs. 39.1 months; p=0.006) and shorter OS (HR-3.7; median OS 26.6 months vs. not reached; p=0.005). Multivariate analysis using the Cox hazard model (n=120) showed that PI-MRD was the most significant and independent high-risk factor for shorter EFS (HR-3.4; p=0.0009) and OS (HR-4.1; p=0.003). Conclusion: Our data showed that the positive status of PIMRD and PCMRD strongly predicts high-risk MPAL patients with short event-free and overall survival. It is independent of age, sex, cytogenetics aberrancies & therapeutic protocol. Thus, PIMRD status was the most relevant Indicator of clinical outcome in MPAL.Keywords: MRD, Minimal residual disease (MRD), Mixed lineage leukemia